NM_005219.5:c.684+239_684+252delTTTTTTTTTTTTTT

Variant names:

Variant summary

Our verdict is . The variant received -4 ACMG points: 0P and 4B. BS1

The NM_005219.5(DIAPH1):c.684+239_684+252delTTTTTTTTTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00257 in 79,770 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00083 ( 0 hom., cov: 16)

Exomes 𝑓: 0.0032 ( 1 hom. )

Consequence

DIAPH1
NM_005219.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.09

Publications

0 publications found

Variant links:

Genes affected

DIAPH1 (HGNC:2876): (diaphanous related formin 1) This gene is a homolog of the Drosophila diaphanous gene, and has been linked to autosomal dominant, fully penetrant, nonsyndromic sensorineural progressive low-frequency hearing loss. Actin polymerization involves proteins known to interact with diaphanous protein in Drosophila and mouse. It has therefore been speculated that this gene may have a role in the regulation of actin polymerization in hair cells of the inner ear. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

DIAPH1 Gene-Disease associations (from GenCC):

DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, PanelApp Australia
progressive microcephaly-seizures-cortical blindness-developmental delay syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia
autosomal dominant nonsyndromic hearing loss 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

DIAPH1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_005219.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00083 (17/20472) while in subpopulation AFR AF = 0.00299 (13/4348). AF 95% confidence interval is 0.00177. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 16. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005219.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DIAPH1	NM_005219.5	MANE Select	c.684+239_684+252delTTTTTTTTTTTTTT	intron	N/A	NP_005210.3
DIAPH1	NM_001079812.3		c.657+239_657+252delTTTTTTTTTTTTTT	intron	N/A	NP_001073280.1	O60610-3
DIAPH1	NM_001314007.2		c.684+239_684+252delTTTTTTTTTTTTTT	intron	N/A	NP_001300936.1	A0A2R8Y5N1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DIAPH1	ENST00000389054.8	TSL:5 MANE Select	c.684+239_684+252delTTTTTTTTTTTTTT	intron	N/A	ENSP00000373706.4	O60610-1
DIAPH1	ENST00000518047.5	TSL:5	c.657+239_657+252delTTTTTTTTTTTTTT	intron	N/A	ENSP00000428268.2	O60610-3
DIAPH1	ENST00000647433.1		c.684+239_684+252delTTTTTTTTTTTTTT	intron	N/A	ENSP00000494675.1	A0A2R8Y5N1

Frequencies

GnomAD3 genomes

AF:

0.000830

AC:

AN:

20476

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00299

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00264

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000780

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00317

AC:

188

AN:

59298

Hom.:

AF XY:

0.00333

AC XY:

110

AN XY:

33080

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00292

AC:

AN:

1026

American (AMR)

AF:

0.00198

AC:

AN:

2528

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

1386

East Asian (EAS)

AF:

0.00

AC:

AN:

2310

South Asian (SAS)

AF:

0.00154

AC:

AN:

10418

European-Finnish (FIN)

AF:

0.00439

AC:

AN:

2736

Middle Eastern (MID)

AF:

0.00510

AC:

AN:

196

European-Non Finnish (NFE)

AF:

0.00385

AC:

138

AN:

35834

Other (OTH)

AF:

0.00384

AC:

AN:

2864

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.379

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000830

AC:

AN:

20472

Hom.:

Cov.:

AF XY:

0.00100

AC XY:

AN XY:

8974

show subpopulations

African (AFR)

AF:

0.00299

AC:

AN:

4348

American (AMR)

AF:

0.00263

AC:

AN:

1140

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

580

East Asian (EAS)

AF:

0.00

AC:

AN:

598

South Asian (SAS)

AF:

0.00

AC:

AN:

310

European-Finnish (FIN)

AF:

0.00

AC:

AN:

288

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0000780

AC:

AN:

12820

Other (OTH)

AF:

0.00

AC:

AN:

206

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over